Cyclopropyl pyridine compounds useful as calcium channel blockers

ABSTRACT

Novel cyclopropyl pyridine compounds useful as calcium channel blockers, pharmaceutical compositions thereof, and methods of treatment are disclosed.

BACKGROUND OF THE INVENTION

Substituted dihydropyridines are known to be useful for reducing bloodpressure, effecting dilation of the coronary vessels, and preventingurospasms. Typical of such substituted dihydropyridines are thosedisclosed in U.S. Pat. Nos. 3,923,818; 3,905,970; 4,044,141; 4,237,137;and 4,285,955. The substituted dihydropyridines disclosed in thesepatents do not include fused cyclopropyl ring structures.

SUMMARY OF THE INVENTION

This invention is directed to novel cyclopropyl pyridine compounds andderivatives thereof. This invention is also directed to pharmaceuticalcompositions and methods of treatment for cardiovascular disorders.

DETAILED DESCRIPTION OF THE INVENTION

The specific cyclopropyl pyridine compounds of this invention arerepresented by the following general structural formula (I): ##STR1##wherein:

R is hydrogen, C₁ -C₈ alkyl, benzyl or C₁ -C₄ carboalkoxy;

R¹ and R⁴ independently are hydrogen, C₁ -C₈ alkyl, C₂ -C₈ alkenyl, C₃-C₈ cycloalkyl or C₁ -C₈ hydroxyalkyl;

R² and R³ independently are C₁ -C₈ alkyl, C₂ -C₈ alkenyl, C₃ -C₈cycloalkyl, C₁ -C₈ hydroxyalkyl, C₁ -C₈ dihydroxyalkyl, C₂ -C₈alkoxyalkyl, C₃ -C₈ alkoxy(alkoxyalkyl) or C₁ -C₈ aminoalkyl wherein theamino group is NR⁵ R⁶ in which R⁵ and R⁶ independently are hydrogen, C₁-C₈ alkyl, C₇ -C₁₄ phenylalkyl or R⁵ and R⁶ together with the N atomform a 5 or 6 membered heterocycle selected from the group consisting ofpiperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperazinyl orN'-C₁ -C₄ -alkylpiperazinyl; and

X and Y independently are hydrogen, C₁ -C₈ alkyl, C₁ -C₈ alkoxy, CF₃,cyano, nitro or halo, (i.e. fluoro, chloro or bromo) or X and Y togetherwith the phenyl group to which they are attached form a naphthyl orbenzoxadiazole group, and pharmaceutically acceptable salts thereof.

The preferred compounds of this invention are those represented by thegeneral structural formula (I) wherein:

R is hydrogen, C₁ -C₈ alkyl or C₁ -C₄ carboalkoxy;

R¹ and R⁴ independently are hydrogen or C₁ -C₈ alkyl;

R² and R³ independently are C₁ -C₈ alkyl or C₁ -C₈ aminoalkyl whereinthe amino group is NR⁵ R⁶ in which R⁵ and R⁶ independently are hydrogen,C₁ -C₈ alkyl or C₇ -C₁₄ phenylalkyl; and

X and Y independently are hydrogen, C₁ -C₈ alkyl, C₁ -C₈ alkoxy, CF₃,cyano, nitro or halo.

The most preferred compounds of this invention are those preferredcompounds wherein: R is hydrogen; R¹, R², R³ and R⁴ independently are C₁-C₈ alkyl and X and Y independently are hydrogen, nitro or C₁ -C₈ alkoxyand are in the 8-and 9-positions respectively.

The compounds of this invention possess asymmetric centers and thusexist in different isomeric forms. All such forms are included withinthe scope of this invention. Specifically, the compounds have anasymmetric center at the carbon atom to which the ester moiety, --CO₂R², is attached. Whenever that ester moiety is below the plane of thepiperidine ring (i.e. down) that stereochemical configuration is denotedas the alpha (α)-isomer. Similarly, whenever that ester moiety is abovethe plane of the piperidine ring (i.e. up) that stereochemicalconfiguration is denoted as the beta (β)-isomer.

Illustrative of the compounds of this invention are the followingcompounds of the formula (I) which are the α-isomer, the β-isomer ormixtures thereof:

(1) Dimethyl1,2,3,6α-tetrahydro-2,4-dimethyl-1,2,6-metheno-3-benzazocine-5,11.alpha.-dicarboxylate[Formula (I) where R is hydrogen, R¹, R², R³ and R⁴ are methyl and X andY are hydrogen];

(2) Dimethyl1,2,3,6α-tetrahydro-2,4-dimethyl-1,2,6-metheno-9-methoxy-3-benzazocine-5,11α-dicarboxylate[Formula (I) where R is hydrogen, R¹, R², R³ and R⁴ are methyl, X ishydrogen and Y is 9-methoxy];

(3) Dimethyl1,2,3,6α-tetrahydro-2,4-dimethyl-1,2,6-metheno-8-nitro-3-benzazocine-5,11α-dicarboxylate[Formula (I) where R is hydrogen, R¹, R², R³ and R⁴ are methyl, X is8-nitro and Y is hydrogen]; and

(4) Trimethyl1,2,3,6α-tetrahydro-2,4-dimethyl-1,2,6-metheno-3-benzazocine-3,5,11.alpha.-tricarboxylate[Formula (I) where R is carbomethoxy, R¹, R², R³ and R⁴ are methyl and Xand Y are hydrogen].

The pharmaceutically acceptable salts are those acid addition salts ofnon-toxic, pharmaceutically acceptable acids and include salts ofinorganic acids such as hydrochloric, hydrobromic, hydroiodic,phosphoric, sulfuric, nitric and the like, and organic acids such astrifluoroacetic and trichloroacetic and the like and include acidsrelated to the pharmaceutically acceptable salts listed in Journal ofPharmaceutical Science, 66, 2 (1977) and incorporated herein byreference.

The compounds of this invention are conveniently prepared from known orreadily obtainable starting materials utilizing the general syntheticpathway described below which is also disclosed and claimed inco-pending patent application Attorney Docket Number 17169 filedcontemperaneously herewith: Ser. No. 655,785 ##STR2##

The aryl dihydropyridine (1) wherein R¹, R², R³, R⁴, X and Y are definedabove, R is hydrogen, R⁷ is C₁ -C₄ alkyl or both R⁷ 's taken togetherare ethylene or propylene and A is oxygen or sulfur is prepared from theappropriately substituted aryl aldehyde utilizing the standard Hantzschreaction conditions. The aryl dihydropyridine (1) wherein R is otherthan hydrogen is obtained by standard alkylation procedures employingthe appropriate alkylating agent, such as alkyl halide, alkyl sulfate,benzyl halide or alkyl haloformate.

The aryl dihydropyridine compound (1) may be treated under mild acidicconditions to remove the acetal or thioacetal protecting group and yieldthe aryl dihydropyridine (2). Mercuric salts may also be employed toremove the thioacetal protecting group.

The aryl dihydropyridine compound (2) is then treated at -10° to 50° C.,preferably ambient temperature, with between 0.5 and 5.0 equivalents,preferably 1.0 equivalent, of p-toluenesulfonylhydrazine (TsNHNH₂) in aninert solvent to yield the aryl dihydropyridine (3). The aryldihydropyridine (3), without isolation or after isolation, is heated at75° to 125° C. either in an inert solvent or neat to afford the compoundof the formula (I). Exemplifying the inert solvents which may beutilized in the cyclization reaction are aromatic hydrocarbons, such asbenzene and toluene. This is the best mode for the preparation of thecompounds of the formula (I).

As indicated above, the compounds of this invention are useful ascalcium channel blockers, and thus have broad pharmacological utility inthat they exhibit (i) pronounced and long-lasting vasodilating effectaccompanied by an energy-sparing effect on cardiac metabolism; (ii)antiarrythmic and antianginal action on cardiac muscle; (iii) vascularspasmolytic action; (iv) antihypertensive action; (v) spasmolytic actionon the smooth muscle of the gastrointestinal and urogenital tracts andthe cerebrovascular and respiratory system; (vi) usefulantihypercholesterolemic and antilipademic action; (vii) protection ofthe ischemic myocardium; (viii) inhibition of irritable bowel syndromeand esophageal spasm; and, (ix) inhibition of migraine. Some of thesecompounds are also useful cardiotonic agents.

The representative compounds of the present invention were found toinhibit vascular calcium contraction, reduce cardiac contractile force,inhibit calcium-mediated tracheal contraction, inhibit calcium uptake inpituitary cells, or displace tritiated nitrendipine from membrane.

The compounds of the present invention can be administered in anysuitable form; e.g. orally, sublingually, transdermally, orparenterally; i.e. intravenously, interperitoneally, etc. Thus, thecompounds can be offered in a form (a) for oral administration e.g. astablets in combination with other compounding ingredients customarilyused such as talc, vegetable oils, polyols, benzyl alcohols, gums,gelatin, starches and other carriers; dissolved or dispersed oremulsified in a suitable liquid carrier; in capsules or encapsulated ina suitable encapsulating material; or (b) for sublingual administration;e.g., nitroglycerine tablets, lactose tablets, and the like, for rapiddissolution or high molecular weight methylcellulose tablets,carboxymethylcellulose tablets, and the like, for slower, time-releasingdelivery; or, (c) for parenteral administration e.g. dissolved ordispersed in a suitable liquid carrier or emulsified.

The pharmaceutical preparations thus described are made following theconventional techniques of the pharmaceutical chemist as appropriate tothe desired end product.

The ratio of active compound to compounding ingredients i.e. carrier,diluent etc. will vary as the dosage form requires. Whatever form isused, the amount of compound of the present invention administeredshould be sufficient to achieve the pharmaceutical and/or therapeuticeffect desired or required in the patient. Generally, doses of thecompounds of the invention of from about 30 to about 3000 mg per day maybe used, preferably about 100 to about 1000 mg per day. Dosages may besingle or multiple depending on the daily total required and the unitdosage administered. Of course, the dose will vary depending upon thenature and severity of disease, weight of the patient, and other factorswhich a person skilled in the art will recognize.

It is often advantageous to administer compounds of this invention incombination with angiotensin converting enzyme inhibitors and/orantihypertensives and/or diuretics and/or β-blocking agents. Forexample, the compounds of this invention can be given in combinationwith such compounds as enalapril, hydralazine hydrochloride,hydrochlorothiazide, methyldopa, timolol, and the like, as well asadmixtures and combinations thereof.

Typically, the individual daily dosages for these combinations can rangefrom about one-fifth of the minimally recommended clinical dosages tothe maximum recommended levels for the entities when they are givensingly. Naturally, these dose ranges can be adjusted on a unit basis asnecessary to permit divided daily dosages and, as noted above, can bevaried depending on the nature and severity of the disease, weight ofpatient, special diets and other factors.

The following Examples are provided to further illustrate the best modecurrently known for preparing the compounds and compositions of thisinvention, but are not to be construed as limiting this invention in anymanner.

EXAMPLE 1 Preparation of Dimethyl1,2,3,6α-tetrahydro-2,4-dimethyl-1,2,6-metheno-3-benzazocine-5,11.alpha.-dicarboxylate

A solution of dimethyl2,6-dimethyl-4-(2-formylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate(1.0 g, 3.0 mmol) and recrystallized p-toluenesulfonylhydrazine (0.60 g,3.2 mmol) in benzene (100 mL) was stirred at room temperature for onehour. The precipitate that formed was removed by filtration, added tofresh benzene (100 mL) and the solution was stirred and refluxed for onehour. The cooled solution was washed with a dilute solution of sodiumbicarbonate, water and brine, was dried over anhydrous magnesiumsulfate, filtered, and was evaporated to dryness. The resulting residuewas then purified by flash chromatography (silica gel, 35% ethyl acetatein hexane) to afford the title compound. Recrystallization of thismaterial from ethyl acetate-hexane gave the title compound; m.p.162°-163.5° C.; IR 3280 (NH); 1720 (CO) cm⁻¹ ; ¹ H NMR δ1.63 (s, 3H, C₂--CH₃), 2.18 (s, 3H, C₄ --CH₃), 2.76 (s, 1H, C₁ --H), 3.74 (s, 3H,OCH₃), 3.82 (s, 3H, OCH₃), 4.16 (s, 1H, NH), 5.25 (s, 1H, C₆ --H),7.06-7.16 (m, 4H, ArH).

Anal. Calcd. for C₁₈ H₁₉ NO₄ : C, 68.99; H, 6.11; N, 4.47; Found: C,69.16; H, 6.30; N, 4.36.

EXAMPLE 2 Preparation of Dimethyl1,2,3,6α-tetrahydro-2,4-dimethyl-9-methoxy-1,2,6-metheno-3-benzazocine-5,11α-dicarboxylate(a) Dimethyl1,4,5,8-tetrahydro-11-methoxy-4,6-dimethyl-1,4,8-metheno-2,3,5-benzotriazocine-7,13α-dicarboxylate(2a)

A solution of dimethyl2,6-dimethyl-4-(2-formyl-4-methoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylate(0.36 g, 1.0 mmol) and recrystallized p-toluenesulfonylhydrazine (0.20g, 1.0 mmol) in benzene (20 mL) was stirred at room temperature for onehour. The solvent was removed under vacuum, and the product was purifiedby flash chromatography (silica gel; 35% ethyl acetate in hexane),followed by dissolving the residue in cold ethyl acetate and byinitiating crystallization by the addition of hexane to afford purecrystalline Compound 2a; m.p. 125° C. (with gas evolution); IR 3330(NH), 1730, 1700 (CO) cm⁻¹ ; ¹ H NMR δ1.57 (s, 3H, C₄ --CH₃), 2.30 (s,3H, C₆ --CH₃), 3.75 (s, 3H, OCH₃), 3.82 (s, 3H, OCH₃), 3.83 (s, 3H,OCH₃), 4.75 (s, 1H, C₈ --H), 4.78 (s, 1H, NH), 6.82 (d,d, 1H, C₁₀ --H),6.83 (s, 1H, C₁ --H), 7.08 (d, 1H, C₉ --H), 7.14 (d, 1H, C₁₂ --H).

Anal. Calcd. for C₁₉ H₂₁ N₃ O₅ : C, 61.44; H, 5.70; N, 11.32; Found: C,61.47; H, 5.90; N, 11.49.

(b) Dimethyl1,2,3,6α-tetrahydro-2,4-dimethyl-9-methoxy-1,2,6-metheno-3-benzazocine-5,11α-dicarboxylate

A solution of dimethyl2,6-dimethyl-4-(2-formyl-4-methoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylate(1.26 g, 3.5 mmol) and recrystallized p-toluenesulfonylhydrazine (0.69g, 3.7 mmol) in benzene (50 mL) was stirred at room temperature for onehour. During this time, a solid crystallized from solution, but thenquickly redissolved. The solution then was refluxed for one hour. Thebenzene solution was washed with water, brine, dried over anhydrousmagnesium sulfate, filtered, and concentrated to dryness. The residuewas purified by flash chromatography (silica gel, 35% ethyl acetate inhexane) followed by recrystallization from ethyl acetate-hexane toafford the title compound; m.p. 160.5°-162° C.; IR 3320 (NH), 1730 (CO)cm⁻¹ ; ¹ H NMR δ1.63 (s, 1H, C₂ --CH₃), 2.18 (s, 3H, C₄ --CH₃), 2.70 (s,1H, C₁ --H), 3.74 (s, 3H, OCH₃), 3.76 (s, 3H, ArOCH₃), 3.80 (s, 3H,OCH₃), 4.18 (s, 1H, NH), 5.16 (s, 1H, C₆ --H), 6.6-7.0 (m, 3H, ArH).

Anal. Calcd. for C₁₉ H₂₁ NO₅ : C, 66.46; H, 6.17; N, 4.08; Found: C,66.50; H, 6.38; N, 3.97.

Alternatively, a sample of the Compound 2a was melted at 125° C. in anoil bath. The residue was chromatographically identical to the titlecompound prepared by the above procedure.

EXAMPLE 3 Preparation of Dimethyl1,2,3,6α-tetrahydro-2,4-dimethyl-8-nitro-1,2,6-metheno-3-benzazocine-5,11α-dicarboxylate(a) 3-Hydroxy-6-nitro-1(3H)-isobenzofuranone (3a)

A mixture of 6-nitro-1(3H)-isobenzofuranone (8.99 g, 50.0 mmol) andN-bromosuccinimide (8.9 g, 50.0 mmol) in carbon tetrachloride (135 mL)was stirred and heated under reflux for one hour during which time thereaction mixture was exposed to the light from a 275 Watt, 125 VoltHanovia sunlamp that was situated 8 inches from the flask. Aftercooling, the succinimide was removed by filtration, and the filtrate wasevaporated in vacuo. The oily residue was mixed with water (200 mL), andthe mixture was refluxed for one hour to give a clear, colorlesssolution. On cooling, the Compound 3a crystallized from solution. Ananalytical sample was prepared by recrystallization from water; m.p.157°-160° C.; IR 3390 cm⁻¹ (OH), 1770 cm⁻¹ (C═O), ¹ H NMR (CDCl₃ -Me₂SO-d₆ -D₂ O) δ6.78 (s, br, 1H, H₃), 7.88 (d, 1H, H₄, J₄,5 =9 Hz), 8.56(d, 1H, H₅, J=9 Hz), 8.62 (s, 1H, H₆).

Anal. Calcd. for C₈ H₅ NO₅ : C, 49.24; H, 2.58; N, 7.18; Found: C,49.39; H, 2.58; N, 7.13.

(b) 2-[1,3-Dithian-2-yl]-5-nitrobenzoic acid (3b)

To an ice-cooled mixture of the Compound 3a (5.00 g, 25.6 mmol) andpropane-1,3-dithiol (2.92 g, 27 mmol) in chloroform (75 mL) was addedboron trifluoride etherate (2 mL). The mixture was stirred and allowedto warm to room temperature. After stirring for 3 hours, most of thesolid had dissolved. Magnesium sulfate was added to dry the solution,and stirring was continued overnight. Filtration and evaporation of thesolvent afforded a light yellow solid. This material was triturated withbutyl chloride to give the Compound 3b; m.p. 192°-194° C.; 1H NMR (CDCl₃+MeSO-d₆ +D₂ O) δ1.8-2.3 (m, 2H, CH₂ CH₂ CH₂), 2.9-3.2 (m, 4H, --CH₂ CH₂CH₂ --), 6.56 (s, 1H, --SCHS--), 7.6-8.8 (m, 3H, ArH).

Anal. Calcd. for C₁₁ H₁₁ NO₄ S₂ : C, 46.30; H, 3.89; N, 4.91; Found: C,46.29; H, 3.84; N, 5.03.

(c) 2-[1,3-Dithian-2-yl]-5-nitrobenzyl alcohol (3c)

To an ice cooled, stirred solution of the Compound 3b (5.00 g, 17.5mmol) in tetrahydrofuran (100 mL) was added dropwise over 30 minutes1.0M BH₃.THF (20 mL). The solution was allowed to warm to roomtemperature and was stirred overnight. Additional 1.0M BH₃.THF (5 mL)was added, and the solution was stirred another 4 hours. Water was addedto hydrolyze the reaction, and the solution then was evaporated todryness. The residue was dissolved in diethyl ether, and this solutionwas washed with a saturated solution of sodium carbonate, brine, and wasdried over anhydrous magnesium sulfate. Evaporation of the solvent andrecrystallization of the product from acetonitrile afforded the Compound3c; m.p. 130°-131° C.; IR 3600 cm⁻¹ (OH); ¹ H NMR (CDCl₃ +D₂ O) δ1.8-2.2(m, 2H, --CH₂ CH₂ CH₂ --), 2.8-3.2 (m, 4H, --CH₂ CH₂ CH₂ --), 4.61 (s,2H, CH₂ O), 5.48 (s, 1H, SCHS), 7.7-8.3 (m, 3H, ArH).

Anal. Calcd. for C₁₁ H₁₃ NO₃ S₂ : C, 48.69; H, 4.83; N, 5.16; Found: C,49.03; H, 5.01; N, 5.01.

(d) 2-[1,3-Dithian-2-yl]-5-nitrobenzaldehyde (3d)

To a solution of 3.47 g (12.8 mmol) of the Compound 3c in methylenechloride (100 mL) was added pyridinium chlorochromate (4.15 g, 19.2mmol). The mixture was stirred for one hour, an additional pyridiniumchlorochromate (2.0 g) was added, and the mixture was stirred 15 hours.Diethyl ether (200 mL) was added to the reaction mixture, and thesolvent was decanted and evaporated. The residue was purified bychromatography (silica gel, chloroform) to afford the Compound 3d aslight yellow crystals; m.p. 99°-101° C.; IR 1730 cm⁻¹ (C═O); ¹ H NMRδ1.7-2.3 (m,2H, --CH₂ CH₂ CH₂ --), 2.8-3.3 (m, 4H,--CH₂ CH₂ CH₂ --),6.13(s, 1H, --SCHS--), 7.8-8.7 (m,--3H, ArH), 10.45 (s, 1H,CHO).

Anal. Calc. for C₁₁ H₁₁ NO₃ S₂ : C, 49.05; H, 4.12; N, 5.20; Found: C,49.16; H, 4.18; N, 5.60.

(e) Dimethyl 4-(2-[13-dithian-2-yl]-5-nitro)phenyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate(3e)

To a solution of the Compound 3d (2.27 g, 8.43 mmol) in methanol (25 mL)was added methyl acetoacetate (0.99 g, 8.5 mmol) andmethyl-β-aminocrotonate (0.99 g, 8.5 mmol). The solution was stirred andrefluxed for 24 hours. The crystalline solid that formed during thereflux period was removed by filtration, and was washed with methanoland dried to afford the Compound 3e; m.p. 278°-279° C.; IR 3435 cm⁻¹(NH), 1695 cm⁻¹ (CO); ¹ H NMR δ1.9-2.3 (m, 2H, --CH₂ CH₂ CH₂ --), 2.37(s, 6H, CH₃), 2.8-3.3 (m, 4H, --CH₂ CH₂ CH₂ --), 3.64 (s, 6H, OCH₃),5.39 (s, 1H, C₄ --H), 5.86 (s, 1H, --SCHS--), 5.92 (s, 1H, NH), 7.8-8.2(m, 3H, ArH).

Anal. Calcd. for C₂₁ H₂₄ N₂ O₆ S₂ : C, 54.29; H, 5.21; N, 6.03; Found:C, 54.20; H, 5.25; N, 6.13.

(f) Dimethyl4-(2-Formyl-5-nitro)phenyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate(3f)

To a vigorously stirred mixture of mercuric oxide (0.93 g, 4.3 mmol) andboron triflouride etherate (0.612 g, 4.31 mmol) in 15% aqueoustetrahydrofuran (10 mL) was added dropwise over 10 minutes, a solutionof the Compound 3e (1.00 g, 2.15 mmol) in tetrahydrofuran (35 mL). Themixture was stirred for 18 hours at room temperature and then wasrefluxed for 15 minutes. The mixture was concentrated to dryness andchloroform was added to the residue. The mixture was filtered, and thefiltrate was washed with a sodium carbonate solution, water, and wasdried over anhydrous magnesium sulfate. Evaporation of the solventafforded the Compound 3f. An analytical sample of the Compound 3f wasprepared by flash chromatography (silica gel, 35% ethyl acetate-hexane),followed by recrystallization from ethyl acetate hexane; m.p. 233°-236°C.; IR 3375 (NH), 1710, 1690, 1645 (CO) cm⁻¹, ¹ H NMR δ2.40 (s, 6H, CH₃), 3.56 (s, 6H, OCH₃), 5.83 (s, 1H, C₄ -H), 6.00 (s, 1H, NH), 7.7-8.3(m, 3H, ArH), 10.65 (s, 1H, CHO).

Anal. Calcd. for C₁₈ H₁₈ N₂ O₇ : C, 57.75; H, 4.84; N, 7.49; Found: C,57.90; H, 4.88; N, 7.57.

(g) Dimethyl1,2,3,6α-tetrahydro-2,4-dimethyl-8-nitro-1,2,6-metheno-3-benzazocine-5,11α-dicarboxylate(3g)

To a solution of the Compound 3f (0.8 g, 2.14 mmol) in benzene (50 mL)was added recrystallized p-toluenesulfonylhydrazine (0.418 g, 2.24mmol). The solution was stirred under nitrogen at room temperature.After about 30 minutes, a crystalline precipitate formed. After stirringanother 45 minutes, a homogeneous solution was obtained. The solutionthen was stirred for an additional 2 hours at room temperature, and for16 hours at reflux. The solvent was removed and the residue was purifiedby flash chromatography (silica gel, 30% ethyl acetate in hexane),followed by recrystallization from ethyl acetate-hexane, to afford puretitle compound; m.p. 177°-179° C.; IR 3310 (NH), 1710, 1640 (CO) cm⁻¹ ;¹ H NMR δ1.68 (s, 3H,C₂ --CH₃), 2.19 (s, 3H,--C₄ --CH₃), 2.80 (s, 1H, C₁--H),3.77 (s, 3H,--OCH₃), 3.85 (s, 3 H, OCH₃), 4.21 (s, 1H, NH), 5.35(s, 1H, C₆ --H), 7.8-8.1 (m, 3H, ArH).

Anal. Calcd. for C₁₈ H₁₈ N₂ O₆ : C, 60.33; H, 5.06; N, 7.82; Found: C,60.48; H, 5.06; N, 7.96.

EXAMPLE 4 Preparation of Trimethyl1,2,3,6α-tetrahydro-2,4-dimethyl-1,2,6-metheno-3-benzazocine-3,5,11.alpha.-tricarboxylate(a) Trimethyl2,6-dimethyl-4-(2-[2-(1,3-dioxolanyl)])phenyl-1,4-dihydropyridine-1,3,5-tricarboxylate(4a)

To a suspension of sodium hydride (61% NaH in mineral oil) (0.393 g) intetrahydrofuran (80 mL) was added dropwise, while stirring magneticallya solution of dimethyl2,6-dimethyl-4-(2-[2-(1,3-dioxolanyl)]phenyl)-1,4-dihydropyridine-3,5-dicarboxylate(3.73 g, 10 mmol) in a mixture of tetrahydrofuran (35 mL) anddimethylformamide (8 mL). After the addition was completed, the mixturewas refluxed for 15 minutes, and then was cooled to room temperature.Methyl chloroformate (0.945 g, 10 mmol) was added and the mixture wasrefluxed for 18 hours. The reaction mixture was concentrated undervacuum and the residue was dissolved in ethyl acetate. This solution waswashed with water (5×100 mL), brine, dried over anhydrous magnesiumsulfate, and concentrated to dryness. The resulting residue was purifiedby chromatography (silica gel, eluting with 30% ethyl acetate in hexane)to afford the Compound 4a. An analytical sample was prepared byrecrystallization from ethyl acetate-hexane; m.p. 120.5° C.; ¹ H NMR δ2.47 (s, 6H, CH₃), 3.73 (s, 6H, OCH₃), 3.83 (s, 3H, NCO₂ CH₃), 4.03-4.24(m, 4H, --OCH₂ CH₂ O--), 5.47 (s, 1H, C₄ --H), 6.26 (s, 1H, OCHO),6.97-7.6 (m, 4H, ArH).

Anal. Calcd. for C₂₂ H₂₅ NO₈ : C, 61.24; H, 5.84; N, 3.25; Found: C,61.02; H, 5.99; N, 3.36.

(b) Trimethyl-2,6-dimethyl-4-(2-[(2-[4-methylphenyl]sulfonylhydrazono)methyl])phenyl-1,3,5-(4H)-pyridinetricarboxylate (4b)

A solution of the Compound 4a (1.15 g, 2.67 mmol) in acetone (100 mL)containing a catalytic amount of p-toluenesulfonic acid monohydrate wasstirred at room temperature for 2.5 hours. The solution was concentratedunder vacuum and the residue was redissolved in methylene chloride.After washing with a dilute solution of sodium bicarbonate, water, andbrine, the solution was dried over anhydrous magnesium sulfate, filteredand concentrated to dryness. The residue was purified by flashchromatography on silica gel. Elution with 50% ethyl acetate-hexaneafforded trimethyl2,6-dimethyl-4-(2-formylphenyl)-1,4-dihydropyridine-1,3,5-tricarboxylate,which was characterized by its NMR spectrum: ¹ H NMR δ2.54 (s, 6H, CH₃),3.68 (s, 6H, OCH₃), 3.90 (s, 3H, NCO₂ CH₃), 5.89 (s, 1H, C₄ --H),7.1-7.9 (m, 4H, ArH), 10.69 (s, 1H, CHO). A solution of 1.70 g (0.0044mol) of this material and recrystallized p-toluenesulfonylhydrazine(0.819 g, 4.4 mmol) benzene (75 mL) was stirred at room temperature for1.5 hours. The solvent was evaporated. The residue was purified by flashchromatography (silica gel, 35% ethyl acetate in hexane) to afford theCompound 4b; m.p. 125°-126° C.; IR 3200 (NH), 1715 (CO) cm⁻¹ ; ¹ H NMRδ2.42 (s, 3H, ArCH₃), 2.46 (s, 6H, CH₃), 3.59 (s, 6H, OCH₃), 3.85 (s,3H, NCO₂ CH₃), 5.58 (s, 1H, C₄ --H), 6.9-8.5 (m, 8H, ArH).

Anal. Calcd. for C₂₇ H₂₉ N₃ O₈ S: C, 58.37; H, 5.26; N, 7.56; Found: C,58.70; H, 5.53; N, 7.56.

(c)Trimethyl-1,2,3,6α-tetrahydro-2,4-dimethyl-1,2,6-metheno-3-benzazocine-3,5,11α-tricarboxylate(4c)

A solution of the Compound 4b (1.1 g, 2.0 mmol) in benzene (100 mL) wasrefluxed for 2 hours. The solution was evaporated to dryness, and theresidue was purified by flash chromatography (silica gel, 30% ethylacetate in hexane) to afford the title compound; m.p. 99°-100° C.; IR1700-1750 cm⁻¹ (CO); ¹ H NMR δ1.68 (s, 3H, C₂ --CH₃), 2.33 (s, 3H, C₄--CH₃), 3.19 (s, 1H, C₁ --H), 3.38 (s, 3H, 11α--CO₂ CH₃), 3.74 (s, 3H,OCH₃), 3.90 (s, 3H, OCH₃), 5.04 (s, 1H, C₆ --H), 7.0-7.2 (m, 4H, ArH).

Anal. Calcd. for C₂₀ H₂₁ NO₆ : C, 64.68; H, 5.70; N, 3.77; Found: C,64.92; H, 5.80; N, 3.42.

EXAMPLE 5 Alternate preparation of Dimethyl1,2,3,6α-tetrahydro-2,4-dimethyl-1,2,6-metheno-3-benzazocine-5,11.alpha.-dicarboxylate

A solution of the Compound 4b (0.111 g 0.2 mmol) and potassium hydroxide(0.014 g, 0.25 mmol) in methanol (10 mL) containing water (0.5 mL) wasstirred at room temperature overnight. After evaporation to dryness, theresidue was taken up in methylene chloride, washed with water, driedsodium sulfate, and evaporated to dryness. The residue was dissolved inbenzene (20 mL), and was refluxed for 2 hours. The solution wasevaporated to dryness, and the residue was purified by flashchromatography (silica gel, 20% ethyl acetate in hexane). The residuewas chromatographically and spectrally identical to the compoundprepared by the direct reaction of p-toluenesulfonylhydrazine withdimethyl-2,6-dimethyl-4-(2-formyl)-phenyl-1,4-dihydropyridine-3,5-dicarboxylateaccording to Example 1.

EXAMPLES 6-21

Utilizing the general procedure of Examples 1, 2 or 3 and starting withappropriately substituted aryl dihydropyridines the following compoundsof the formula (I) are prepared.

    __________________________________________________________________________    Compound                                                                            R   R.sup.1  R.sup.2    R.sup.3       R.sup.4                                                                          X   Y                          __________________________________________________________________________    6     H   Et       Et         Et            Et H   H                          7     H   H        Me         Me            Et H   9-OMe                      8     Me  Me                                                                                      ##STR3##  Me            Me H   H                          9     PhCH.sub.2                                                                        Me       Et         Et            Me H   9-NO.sub.2                 10    H   Me       Me         CH.sub.2 CH.sub.2 OCH.sub.3                                                                 Me H   7-CF.sub.3                 11    CO.sub.2 Me                                                                       Me                                                                                      ##STR4##                                                                                 ##STR5##     Me H   H                          12    CO.sub.2 Et                                                                       Me       Me         Me            Me H   H                          13    H   CH.sub.2 CHCH.sub.2                                                                    Me         Me            Me 8-Cl                                                                              9-Cl                       14    H   CH.sub.2 OH                                                                            Et         Et            Me H   H                          15    H                                                                                  ##STR6##                                                                              Me         Me            Me 8-OMe                                                                             H                          16    Et  Me       CH.sub.2 CHCH.sub. 2                                                                     CH.sub.2 CHCH.sub.2                                                                         Me H   8-Me                       17    H   Me       CH.sub.2 CH.sub.2 OH                                                                     Me            Me H   7-Cl                       18    PhCH.sub.2                                                                        Me       Me         CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2                                          OCH.sub.3     Me H   H                          19    H   Me       CH.sub.2 CH.sub.2 NMe.sub.2                                                              CH.sub.2 CH.sub.2 NMe.sub.2                                                                 Me H   8-CF.sub.3                 20    H   Me                                                                                      ##STR7##  Et            Me 7-CN                                                                              H                          21    H   Me                                                                                      ##STR8##                                                                                 ##STR9##     Me H   H                          __________________________________________________________________________

It should be noted that for the preparation of Compounds 8, 14 and 17the hydroxyalkyl moiety is acylated with acetic anhydride prior tocyclization and then deacylated with sodium hydroxide.

EXAMPLE 21

As a specific embodiment of a composition of this invention an activeingredient, such as dimethyl1,2,3,6α-tetrahydro-2,4-dimethyl-1,2,6-metheno-3-benzazocine-5,11.alpha.-dicarboxylate,is formulated to yield 5000 compressed tablets, each containing 50 mg ofthe active ingredient, as follows:

    ______________________________________                                        Active ingredient       250    grams                                          Starch                  70     grams                                          Dibasic calcium phosphate hydrous                                                                     500    grams                                          Calcium stearate        2.5    grams                                          ______________________________________                                    

What is claimed is:
 1. A compound represented by the following generalstructural formula (I): ##STR10## wherein: R is hydrogen, C₁ -C₈ alkyl,benzyl or C₁ -C₄ carboalkoxy;R¹ and R⁴ independently are hydrogen, C₁-C₈ alkyl, C₂ -C₈ alkenyl, C₃ -C₈ cycloalkyl or C₁ -C₈ hydroxyalkyl; R²and R³ independently are C₁ -C₈ alkyl, C₂ -C₈ alkenyl, C₃ -C₈cycloalkyl, C₁ -C₈ hydroxyalkyl, C₁ -C₈ dihydroxyalkyl, C₂ -C₈alkoxyalkyl, C₃ -C₈ alkoxy(alkoxyalkyl) or C₁ -C₈ aminoalkyl wherein theamino group is NR⁵ R⁶ in which R⁵ and R⁶ independently are hydrogen, C₁-C₈ alkyl, C₇ -C₁₄ phenylalkyl or R⁵ and R⁶ together with the N atomform a 5 or 6 membered heterocycle selected from the group consisting ofpiperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperazinyl orN'-C₁ -C₄ -alkylpiperazinyl; and X and Y independently are hydrogen, C₁-C₈ alkyl, C₁ -C₈ alkoxy, CF₃, cyano, nitro or halo, or X and Y togetherwith the phenyl group to which they are attached form a naphthyl orbenzoxadiazole group, or a pharmaceutically acceptable salt thereof. 2.A compound represented by the following general structural formula (I):##STR11## wherein R is hydrogen, C₁ -C₈ alkyl or C₁ -C₄ carboalkoxy;R¹and R⁴ independently are hydrogen or C₁ -C₈ alkyl; R² and R³independently are C₁ -C₈ alkyl or C₁ -C₈ aminoalkyl wherein the aminogroup is NR⁵ R⁶ in which R⁵ and R⁶ independently are hydrogen, C₁ -C₈alkyl or C₇ -C₁₄ phenylalkyl; and X and Y independently are hydrogen, C₁-C₈ alkyl, C₁ -C₈ alkoxy, CF₃, cyano, nitro or halo.
 3. A compound ofclaim 2 wherein: R is hydrogen; R¹, R², R³ and R⁴ independently are C₁-C₈ alkyl; and X and Y independently are hydrogen, nitro or C₁ -C₈alkoxy and are in the 8-and 9 positions respectively.
 4. A compound ofclaim 3 which is dimethyl1,2,3,6α-tetrahydro-2,4-dimethyl-1,2,6-metheno-3-benzazocine-5,11.alpha.-dicarboxylate.5. A compound of claim 3 which is dimethyl1,2,3,6α-tetrahydro-2,4-dimethyl-1,2,6-metheno-9-methoxy-3-benzazocine-5,11α-dicarboxylate.6. A compound of claim 3 which is dimethyl1,2,3,6α-tetrahydro-2,4-dimethyl-1,2,6-metheno-8-nitro-3-benzazocine-5,11α-dicarboxylate.7. A compound of claim 2 which is trimethyl1,2,3,6α-tetrahydro-2,4-dimethyl-1,2,6-metheno-3-benzazocine-3,5,11.alpha.-tricarboxylate.8. A pharmaceutical composition, useful in the treatment ofcardiovascular disorders comprising a nontoxic therapeutically effectiveamount of a compound according to claim 1 in an admixture with apharmaceutically acceptable carrier.
 9. A method of treatment forcardiovascular disorders which comprises administering to a subject inneed of such of such treatment a nontoxic therapeutically effectiveamount of a compound according to claim 1.